2 Physiology and Pathophysiology of Blood Cells

Introduction to the Physiology and Pathophysiology of the Hematopoietic System

The reason why quantitative and qualitative diagnosis based on the cellular components of the blood is so important is that blood cells are easily accessible indicators of disturbances in their organs of origin or degradation—which are much less easily accessible. Thus, disturbances in the erythrocyte, granulocyte, and thrombocyte series allow important conclusions to be drawn about bone marrow function, just as disturbances of the lymphatic cells indicate reactions or disease states of the specialized lymphopoietic organs (basically, the lymph nodes, spleen, and the diffuse lymphatic intestinal organ).

Cell Systems

All blood cells derive from a common stem cell. Under the influences of local and humoral factors, stem cells differentiate into different

Fig. 1 Model of cell lineages ! in hematopoiesis

Pluripotent lymphatic stem cells

Pluripotent hemato-

NK cells

T-lymphopoiesis

B-lymphopoiesis

T-lymphoblasts B-lymphoblasts

NK cells

T-lymphocytes

B-lymphocytes

Plasma cells

Introduction to the Physiology and Pathophysiology	3

cell lines (Fig. 1). Erythropoiesis and thrombopoiesis proceed independently once the stem cell stage has been passed, whereas monocytopoiesis and granulocytopoiesis are quite closely “related.” Lymphocytopoiesis is the most independent among the remaining cell series. Granulocytes, monocytes, and lymphocytes are collectively called leukocytes (white blood cells), a term that has been retained since the days before staining

	Omnipotent			Pluripotent myeloid
	stem cells
				stem cells
	poietic stem cells
			Granulopoiesis
	Basophils	Eosinophils	monopoiesis		Thrombopoiesis	Erythropoiesis
			Monopoiesis	Granulopoiesis
			Monoblasts	Myeloblasts	Mega-	Proery-
					karyoblasts	throblasts
	Basophilic	Eosinophilic		Promyelocytes		Erythroblasts
	promyelocytes promyelocytes			Myelocytes	Mega-
			Promonocytes
				Metamyelocytes	karyocytes
				Cells with band nuclei
	Basophilic	Eosinophilic	Monocytes	Neutrophilic	Thrombo-	Erythrocytes
	segmented	segmented		granulocytes	cytes
	granulocytes	granulocytes		with segmented
				nuclei

Macrophages

4 Physiology and Pathophysiology of Blood Cells

methods were available, when the only distinction that could be made was between erythrocytes (red blood cells) and the rest.

All these cells are eukaryotic, that is, they are made up of a nucleus, sometimes with visible nucleoli, surrounded by cytoplasm, which may include various kinds of organelles, granulations, and vacuoles.

Despite the common origin of all the cells, ordinary light microscopy reveals fundamental and characteristic differences in the nuclear chromatin structure in the different cell series and their various stages of maturation (Fig. 2).

The developing cells in the granulocyte series (myeloblasts and promyelocytes), for example, show a delicate, fine “net-like” (reticular) structure. Careful microscopic examination (using fine focus adjustment to view different depth levels) reveals a detailed nuclear structure that resembles fine or coarse gravel (Fig. 2a). With progressive stages of nuclear maturation in this series (myelocytes, metamyelocytes, and band or staff cells), the chromatin condenses into bands or streaks, giving the nucleus— which at the same time is adopting a characteristic curved shape—a spotted and striped pattern (Fig. 2b).

Lymphocytes, on the other hand—particularly in their circulating forms—always have large, solid-looking nuclei. Like cross-sections through geological slate, homogeneous, dense chromatin bands alternate with lighter interruptions and fissures (Fig. 2c).

Each of these cell series contains precursors that can divide (blast precursors) and mature or almost mature forms that can no longer divide; the morphological differences between these correspond not to steps in mito-

a	Nucleus (with
Vacuoles
	delicate reticular
	chromatin structure)
	Cytoplasm
	Nucleolus
	Cytoplasmic granules
b	c

Lobed nucleus with	Coarse chromatin
banded chromatin	structure
structure

Fig. 2 Principles of cell structure with examples of different nuclear chromatin structure. a Cell of the myeloblast to promyelocyte type. b Cell of the myelocyte to staff or band cell type. c Cell of the lymphocyte type with coarsely structured chromatin

Introduction to the Physiology and Pathophysiology	5

sis, but result from continuous “maturation processes” of the cell nucleus and cytoplasm. Once this is understood, it becomes easier not to be too rigid about morphological distinctions between certain cell stages. The blastic precursors usually reside in the hematopoietic organs (bone marrow and lymph nodes). Since, however, a strict blood–bone marrow barrier does not exist (blasts are kept out of the bloodstream essentially only by their limited plasticity, i.e., their inability to cross the diffusion barrier into the bloodstream), it is in principle possible for any cell type to be found in peripheral blood, and when cell production is increased, the statistical frequency with which they cross into the bloodstream will naturally rise as well. Conventionally, cells are sorted left to right from immature to mature, so an increased level of immature cells in the bloodstream causes a “left shift” in the composition of a cell series—although it must be said that only in the precursor stages of granulopoiesis are the cell morphologies sufficiently distinct for this left shift to show up clearly.

The distribution of white blood cells outside their places of origin cannot be inferred simply from a drop of capillary blood. This is because the majority of white cells remain out of circulation, “marginated” in the epithelial lining of vessel walls or in extravascular spaces, from where they may be quickly recruited back to the bloodstream. This phenomenon explains why white cell counts can vary rapidly without or before any change has taken place in the rate of their production.

Cell functions. A brief indication of the functions of the various cell groups follows (see Table 1).

Neutrophil granulocytes with segmented nuclei serve mostly to defend against bacteria. Predominantly outside the vascular system, in “inflamed” tissue, they phagocytose and lyse bacteria. The blood merely transports the granulocytes to their site of action.

The function of eosinophilic granulocytes is defense against parasites; they have a direct cytotoxic action on parasites and their eggs and larvae. They also play a role in the down-regulation of anaphylactic shock reactions and autoimmune responses, thus controlling the influence of basophilic cells.

The main function of basophilic granulocytes and their tissue-bound equivalents (tissue mast cells) is to regulate circulation through the release of substances such as histamine, serotonin, and heparin. These tissue hormones increase vascular permeability at the site of various local antigen activity and thus regulate the influx of the other inflammatory cells.

The main function of monocytes is the defense against bacteria, fungi, viruses, and foreign bodies. Defensive activities take place mostly outside the vessels by phagocytosis. Monocytes also break down endogenous cells (e.g., erythrocytes) at the end of their life cycles, and they are assumed to perform a similar function in defense against tumors. Outside the bloodstream, monocytes develop into histiocytes; macrophages in the

6 Physiology and Pathophysiology of Blood Cells

endothelium of the body cavities; epithelioid cells; foreign body macrophages (including Langhans’ giant cells); and many other cells.

Lymphocytes are divided into two major basic groups according to function.

Thymus-dependent T-lymphocytes, which make up about 70% of lymphocytes, provide local defense against antigens from organic and inorganic foreign bodies in the form of delayed-type hypersensitivity, as classically exemplified by the tuberculin reaction. T-lymphocytes are divided into helper cells and suppressor cells. The small group of NK (natural killer) cells, which have a direct cytotoxic function, is closely related to the T-cell group.

The other group is the bone-marrow-dependent B-lymphocytes or B- cells, which make up about 20% of lymphocytes. Through their development into immunoglobulin-secreting plasma cells, B-lymphocytes are responsible for the entire humoral side of defense against viruses, bacteria, and allergens.

Table 1 Cells in a normal peripheral blood smear and their physiological roles

Cell type	Function		Count
			(% of leuko-
			cytes)
Neutrophilic band	Precursors of segmented cells		0–4%
granulocytes (band	that provide antibacterial
neutrophil)	immune response
Neutrophilic segmented	Phagocytosis of bacteria;		50–70%
granulocyte (segmented	migrate into tissue for this pur-
neutrophil)	pose
Lymphocytes	B-lymphocytes (20% of
(B- and T-lymphocytes,	lymphocytes) mature and
morphologically indistin-	form plasma cells !antibody
			20–50%
guishable)	production.
	T-lymphocytes (70%): cyto-
	toxic defense against viruses,
	foreign antigens, and tumors.
Monocytes	Phagocytosis of bacteria, pro-		2–8%
	tozoa, fungi, foreign bodies.
	Transformation in target tissue
Eosinophilic granulocytes	Immune defense against para-		1–4%
	sites, immune regulation
Basophilic granulocytes	Regulation of the response to		0–1%
	local inflammatory processes